Understanding and controlling the transition from dysplasic growth to neoplasia in the gastrointestinal tract requires coordinated evaluation of the molecular and anatomic markers of disease using both specific biochemical probes to recognize alterations in cellular physiology and cell surface markers, and established technologies that can detect and interrogate both structure and function. To improve detection of Gl cancers we propose to perform collaborative translational research in optical imaging and spectroscopy using multimodal platforms for the detection of early neoplastic lesions arising from the Gl epithelium. We have established an integrated Specialized Research Resource Center comprised of investigators from Stanford University, Vanderbilt University, University of Florida and University of California, Davis. The overarching aim of this program is develop a consensus process and methodology based on optics and ultrasound to optimize detection of early molecular markers of disease by examining molecular markers in the context of ultrastructural changes. We will use fluorescence contrast agents for functional analyses and both optics and ultrasound for assessing anatomic changes. Aided by wide-field fluorescence endoscopy and ultrasound, fiberbased optical probes will be used to analyze the molecular signatures of disease. The engineering components of this program are aimed at systems integration using established white light/fluorescence endoscopy and ultrasound systems and state-of-the-art miniaturized sensors for high resolution/high sensitivity detection of molecular probes directed at markers of cancer. The probe chemistries are well-established and based on existing targets. Probes include peptides, selected for binding to dysplastic epithelium, and compounds directed at COX-2 as an intracellular marker of malignancy. The program provides an infrastructure to support subprojects that are aimed at translating well-developed tools and techniques into the clinic. In each subproject, a strong foundation of established technologies supports innovative approaches to improve integration and enhance early detection. The clinical team consists of endoscopists with a track record of translational research that will evaluate the integrated tools and reagents in patients. We have a strong pathology team comprised of pathologists with expertise in optical imaging and spectroscopy to facilitate validation with histopathological standards. The major project in this program has four specific aims that are each addressed in a multidisciplinary and directed approach. These include: i) validation of molecular markers of Gl cancer as targets for imaging and therapy, ii) advancing molecular probes and integrated instrument combinations for imaging and therapy of Gl cancer, iii) optimization of probe-therapy combinations based on validated molecular markers, and iv) clinically evaluate instrument and probe combinations. These aims are supported by two task specific projects and 5 cores with oversight by an executive committee.